Cartilage is composed of chondrocytes (cells derived from mesenchymal cells) which are dispersed in the matrix (a firm, gel-like ground substance). The cartilaginous matrix is produced by these cells and comprises mainly Type II collagen fibers (except fibrocartilage which also contains Type I collagen fibers), proteoglycans, and elastin fibers. Cartilage is found, among other places, in the joints, the ribcage, the ears, the nose, the throat, the trachea and the intervertebral disks. There are three main types of cartilage, hyaline, elastic and fibrocartilage, providing notably different functional properties according to their histological morphology. Articular cartilage, for instance, is a hyaline cartilage, having viscoelastic properties, covering the articular surfaces of bones. The main purpose of articular cartilage is to provide smooth surfaces in order to ensure nearly frictionless movement of articulating bones.
Cartilage disorders broadly refers to diseases characterized by degeneration/disintegration of cartilage and abnormalities in the connective tissues which are manifested by inflammation, pain, stiffness and limitation of motion of the affected body parts. These disorders can be due to a pathology or can be the result of trauma or injury. Mature cartilage has very limited ability to self-repair, notably because mature chondrocytes have little potential for proliferation due to limited supply with nutrients linked to the absence of blood vessels in cartilage. Replacement of damaged cartilage, in particular articular cartilage, caused either by injury or disease, is a major challenge for physicians, and available surgical treatment procedures are considered unpredictable and effective for only a limited time in younger patients without osteoarthritic changes. Therefore, the majority of patients either do not seek treatment or are counseled to postpone treatment for as long as possible. When treatment is required, the standard procedure is age-dependent and varies between total or partial joint replacement, transplantation of pieces of cartilage or chondrocytes or marrow-stimulating techniques (such as microfracture). Microfracture is a cheap and common procedure that involves penetration of the subchondral bone to stimulate cartilage deposition by bone marrow-derived stem cells. However, it has been shown that this technique does not sufficiently repair the chondral defect and the new cartilage formed is mainly fibrocartilage, resulting in a short-lived repair tissue. Indeed, fibrocartilage does not have the same biomechanical properties as hyaline articular cartilage and often lacks proper lateral integration into the surrounding cartilage. For this reason, the newly synthesized fibrocartilage may break down more easily (expected time frame: 5-10 years).
For patients with osteoarthritis (OA) all these cartilage repair techniques fail. The remaining non-surgical treatment consists notably of physical therapy, lifestyle modification (e.g., body weight reduction), supportive devices, oral drugs (e.g., non-steroidal anti-inflammatory drugs), injection of drugs (e.g., hyaluronic acid and corticoids), and food suplementation. All these treatments are unable to stop OA disease progression. If the pain therapy also fails, surgery, such as joint replacement or high tibial osteotomy for the knee joint, is the remaining option for the patients. Tibial or femoral osteotomies (cutting the bone to rebalance joint wear) may reduce symptoms, help to maintain an active lifestyle, and delay the need for total joint replacement. Total joint replacement can provide relief for the symptoms of advanced osteoarthritis, but generally requires a significant change in a patient's lifestyle and/or activity level.
Current available drug treatments are mainly directed to pain relief. At this time, there is no commercially available treatment that restores the cartilage damage (Lotz, 2010).
Interleukin-1 alpha (IL-1α) and interleukin-1 beta (IL-1β) are naturally occurring agonists of the type I IL-1 receptor (IL-1RA). Overexpression of proinflammatory cytokines, such as IL-1, has been shown to play a major role in the pathogenesis of immunoinflammatory diseases such as rheumatoid arthritis (RA) (Bingham, 2002) or osteoarthritis (OA) (Lee et al., 2013). The clinical application of antagonizing IL-1α and IL-1β in RA has been investigated with anakinra (Kineret™), a recombinant, non-glycoslyated form of human IL-1ra. The use of this therapeutic protein has led to a reduction in frequency and severity of joint damage in RA patients (Bresnihan, 2002; St. Clair, 2002), as well as pain reduction (Mertens et al., 2009). This molecule has been approved in 2001 in the treatment of some types of RA. Although IL-1 is also involved in OA, anakinra therapy is not significantly associated with improvements in OA symptoms compared with placebo, although a tendency toward pain reduction with anakinra 150 mg versus placebo was noted (Chevalier et al., 2009).
Fibroblast Growth Factor 18 (FGF-18) is a member of the Fibroblast Growth Factor (FGF) family of proteins, closely related to FGF-8 and FGF-17. It has been shown that FGF-18 is a proliferative agent for chondrocytes and osteoblasts (Ellsworth et al., 2002; Shimoaka et al., 2002). FGF-18 has been proposed for the treatment of cartilage disorders such as osteoarthritis and cartilage injury, either alone (WO2008/023063) or in combination with hyaluronic acid (WO2004/032849).
Various dosing regimens have been suggested for FGF-18. For instance, Moore et al. (2005) disclosed administration twice weekly for 3 weeks, and WO2008/023063 taught administration once a week for 3 weeks. This last dosing regimen has been investigated in clinical trials (for more details see for instance NCT01033994, NCT00911469 and NCT01066871).
Although the dosing regimen described in WO2008/023063 gives good results in articular cartilage repair, there is still a risk of acute synovitis. For this reason, there is a need for a method of decreasing risk of treatment-related acute synovitis as well as increasing patient tolerance to intra-articular injection, while maintaining the efficacy for the treatment of cartilage disorders, notably via chondrocyte proliferation and subsequent cartilage repair. Such a method should not only allow articular cartilage repair, possibly in the absence of synovitis, but also allow reformation of new cartilage having good properties (i.e., mainly hyaline cartilage). Indeed, generation of said hyaline cartilage is valuable both as a therapeutic and as a component for biological matrices (Getgood et al., 2010). There is also a need for a method of decreasing pain/improving function, while maintaining the efficacy for the treatment of cartilage disorders. Indeed, pain is not only very often associated with cartilage disorders but represents the leading symptom for clinical detection of these disorders.